Recent studies showed that immune cells recognize redox-active cytotoxic extracellular Hb (metHb)bound to pathogen-associated molecular patterns (PAMPs), and the available information is limited to experiments performed in defined conditions using single cell lines. Therefore, a systemic approach targeting primary whole blood cells is required to better understand the cellular immune defence against metHb and PAMPs, when it is under a haemolytic infection.

A team led by Prof DING Jeak Ling from the Department of Biological Sciences in NUS found that metHb activates NFk-B in TLR2-expressing HEK293 cells but not in normal or TLR9-expressing HEK293 cells. Treatment of isolated neutrophils with metHb increased production of ROS and expressions of IL-8, TNFa, and CD11b, which were further enhanced by metHb+LTA complex. While LTA stimulated the survival of neutrophils, it caused apoptotic cell death when complexed with metHb.The activation of neutrophils by metHb+LTA was subdued by the presence of other types of white blood cells. The team’s findings indicate that metHb and metHb+LTA complex are ligands of TLR2, inducing an unconventional TLR signalling pathway. Neutrophils are a highly sensitive cell type responsive to metHb+LTA complex. During a haemolytic infection, white blood cells in the vicinity crosstalk to modulate neutrophil TLR-signalling induced by metHb and LTA (see Figure).

This research has been published in EBioMedicine, an Open Access journal with Cell Press and The Lancet editorial influence.

This image shows that during a haemolytic infection, white blood cells in the vicinity crosstalk to modulate neutrophil TLR-signalling induced by metHb and LTA. [Image credit: Sae-Kyung LEE]